Oroxylin A activates PKM1/HNF4 alpha to induce hepatoma differentiation and block cancer progression

Abstract

Liver cancer is the second cause of death from cancer worldwide, without effective treatment. Traditional chemotherapy for liver cancer has big side effects for patients, whereas targeted drugs, such as sorafenib, commonly have drug resistance. Oroxylin A (OA) is the main bioactive flavonoids of Scutellariae radix, which has strong anti-hepatoma effect but low toxicity to normal tissue. To date, no differentiation-inducing agents have been reported to exert a curative effect on solid tumors. Here our results demonstrated that OA restrained the proliferation and induced differentiation of hepatoma both in vitro and in vivo, via inducing a high PKM1 (pyruvate kinase M1)/PKM2 (pyruvate kinase M2) ratio. In addition, inhibited expression of polypyrimidine tract-binding protein by OA was in charge of the decrease of PKM2 and increase of PKM1. Further studies demonstrated that increased PKM1 translocated into the nucleus and bound with HNF-4α (hepatocyte nuclear factor 4 alpha) directly, promoting the transcription of HNF-4α-targeted genes. This work suggested that OA increased PKM1/PKM2 ratio, resulting in HNF-4α activation and hepatoma differentiation. Especially, OA showed reliable anticancer effect on both human primary hepatocellular carcinoma cells and patient-derived tumor xenograft model for hepatoma, and slowed down the development of primary hepatoma, suggesting that OA could be developed into a novel differentiation inducer agent for hepatoma.

Hepatocyte Nuclear Factor 4 Alpha Activation Is Essential for Termination of Liver Regeneration in Mice

“…HNF4α regulates genes involved in xenobiotic metabolism, carbohydrate metabolism, fatty acid metabolism, bile acid synthesis, blood coagulation, and ureagenesis . Expression of HNF4α induces hepatocyte‐like characteristics in induced pluripotent stem cells, and forced expression of HNF4α induces differentiation and decrease cancer progression in hepatocellular carcinomas (HCCs) . Furthermore, decreased HNF4α expression leads to loss of hepatic function and causes decompensation in cirrhotic rats …”

“…progression in hepatocellular carcinomas (HCCs). (7,8) Furthermore, decreased HNF4α expression leads to loss of hepatic function and causes decompensation in cirrhotic rats. (9) Recent studies from our laboratory and others have revealed antiproliferative properties of HNF4α (10,11) in the liver.…”

Tipping-point analysis uncovers critical transition signals from gene expression profiles

“…Furthermore, there is no significant differences in HNF4A expression between HR and non-HR patients, explaining why few literature describing HNF4A in NB. These suggest a complex if not contradictory role of HNF4α in differentiation that has recently emerged in cancer of multiple organs and embryonal cell (Chiba, Itoh et al, 2005, Lucas, Grigo et al, 2005, Sun, Xu et al, 2019, Tanaka, Jiang et al, 2006, Wei, Dai et al, 2017.…”

Oroxylin A inhibits Kaposi's sarcoma‐associated herpes virus (KSHV) vIL‐6–mediated lymphatic reprogramming of vascular endothelial cells through modulating PPARγ/Prox1 axis

“…Oroxylin A is one of the major flavonoids which are the most common active ingredients in the root bark of O. indicum . It has been widely studied and proved to possess a wide spectrum of pharmacological properties, such as proapoptotic and anti‐invasive activities . Several previous reports suggested that oroxylin A was a potential anti‐invasive agent.…”

“…12 It has been widely studied and proved to possess a wide spectrum of pharmacological properties, such as proapoptotic and anti-invasive activities. 14,15 Several previous reports suggested that oroxylin A was a potential anti-invasive agent. But whether oroxylin A can inhibit neovascularization, especially lymphangiogenesis in some chronic malignant diseases is still unknown.…”